Abstract
Oxidation of low density lipoprotein (LDL) may be of critical importance in the pathogenesis of atherosclerosis. Recent studies suggest that oxidized phospholipids render LDL atherogenic. However, both the structures and the physiologically relevant pathways for the formation of modified phospholipids in oxidized LDL remain poorly understood. We previously showed that p-hydroxyphenylacetaldehyde (pHA) is the major product of L-tyrosine oxidation by the myeloperoxidase/hydrogen peroxide/chloride system of phagocytes. In the current studies, we demonstrate that this reactive aldehyde targets the aminophospholipids of LDL in vitro and in vivo. Activated human neutrophils generated pHA-ethanolamine, the reduced adduct of pHA with the amino group of phosphatidylethanolamine, on LDL phospholipids by a reaction that required myeloperoxidase, H(2)O(2), and L-tyrosine. The cellular system could be replaced by HOCl and L-tyrosine but not by a wide variety of other oxidation systems, indicating that pHA-ethanolamine is a specific marker for covalent modification of aminophospholipids by myeloperoxidase. To determine whether aldehydes modify aminophospholipids in vivo, we quantified levels of pHA-ethanolamine in acid hydrolysates of reduced lipid extracts through isotope dilution gas chromatography/mass spectrometry. Circulating LDL contained undetectable levels of pHA-modified phospholipid (<0.1 mmol/mol). In contrast, the concentration of pHA-ethanolamine in LDL isolated from human atherosclerotic lesions was strikingly elevated (4.5 mmol/mol). Collectively, these results demonstrate a novel, myeloperoxidase-based mechanism for modifying the amino group of LDL phospholipids. They also offer the first evidence that myeloperoxidase may damage LDL lipids in vivo, raising the possibility that aldehyde-modified aminophospholipids play a role in inflammation and vascular disease.
Highlights
An elevated level of low density lipoprotein (LDL),1 the major blood transporter of cholesterol, is a major risk factor for atherosclerosis [1]
Its concentration in LDL isolated from atherosclerotic intima was 40 times greater than the detection limit (4.5 Ϯ 4.1 mmol/mol of ethanolamine, mean Ϯ S.D.). These results indicate that pHA, a reactive aldehyde generated by myeloperoxidase, modifies LDL aminophospholipids in the human artery wall
We demonstrate that pHA generated by the myeloperoxidase system of phagocytes forms a Schiff base with the amino group of phosphatidylethanolamine in LDL
Summary
An elevated level of low density lipoprotein (LDL), the major blood transporter of cholesterol, is a major risk factor for atherosclerosis [1]. One potentially important class of reactions that render LDL atherogenic involves aldehydes, which are generated through decomposition of peroxidized lipids [2,3,4] These products can attract monocytes into the artery wall [5, 6] and covalently modify LDL [7,8,9], rendering it a ligand for macrophage scavenger receptors. Monoclonal antibodies that bind to epitopes on oxidized phospholipids block the uptake and degradation of oxidized LDL by mouse peritoneal macrophages [23] These observations have led to the proposal that modification of the lipid moieties is involved in recognition of copper-oxidized LDL by scavenger receptors [21,22,23], the nature of these modified lipids has not yet been established. The enzyme uses H2O2 generated by phagocytes to convert chloride ion to hypochlorous acid (HOCl), a potent cytotoxin [26, 27, 32]
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